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Blood, 1 August 2006, Vol. 108, No. 3, pp. 1030-1036.
Prepublished online as a Blood First Edition Paper on April 6, 2006; DOI 10.1182/blood-2005-12-007005.
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Submitted December 8, 2005
Accepted March 14, 2006
The Flt3 receptor tyrosine kinase collaborates with
NUP98-HOX fusions in Acute Myeloid Leukemia
Lars Palmqvist, Bob Argiropoulos, Nicolas Pineault, Carolina Abramovich, Laura M Sly, Gerald Krystal, Adrian Wan, and R Keith Humphries*
Institute of Laboratory Medicine, Sahlgrenska University Hospital, Goteborg, Sweden
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
* Corresponding author; email: khumphri{at}bccrc.ca.
In leukemogenesis several genetic changes conferring a
proliferative and/or survival advantage to hematopoietic
progenitor cells in addition to a block in
differentiation are required. Here, we demonstrate that
overexpression of the wild type (wt) Flt3 receptor
tyrosine kinase collaborates with NUP98-HOX fusions
(NUP98-HOXA10 and NUP98-HOXD13) to induce aggressive
AML. We used a mouse transplantation model to show their
synergism in co-transduced bone marrow cells as well as
in a cellular model of leukemic progression.
Furthermore, our data support the finding that Meis1
overexpression leads to marked elevation in Flt3
transcription and extend it to the context of NUP98-HOX-
induced leukemia. Together, these results support a
multi-step model where the synergism between NUP98-HOX
and wt-Flt3 is the result of the ability of Flt3 to
increase proliferation of myeloid progenitors blocked in
differentiation by NUP98-HOX fusions and reveal a direct
role for wt-Flt3 in the pathobiology of AML. Given the
similarities in the leukemogenic role of native HOX and
NUP98 fused HOX genes, our results underscore the
clinical significance of the recurrent co-overexpression
of wt-FLT3 and HOX in human leukemia and suggest that
specific FLT3 inhibitors could be useful in treatment of
HOX-induced AML or ALL.
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